The firefighters were searching for people who may have been trapped inside when the roof gave way, Fire Chief Terry Garrison told a news conference.
"They were in the highest amount of risk possible because we thought we had some civilians in the structure," he said. "Unfortunately, the building had much more fire in it than we originally thought. The structure collapsed, and our members, while trying to save lives, were trapped."
It was the worst loss of firefighters in a single incident in the department's history.
At least one of the injured firefighters was in critical condition at a local hospital, officials said.
The department said 13 firefighters were transported from the afternoon blaze with various injuries including heat exhaustion. They have not identified the injured firefighters.
Texans are still reeling from the loss of first responders, including firefighters and paramedics, when a fertilizer plant in West exploded on April 17.
Garrison said the cause of the fire at the Bhojan Restaurant and Southwest Inn was under investigation. The fire was reported just after midday in Houston and was under control by mid-afternoon.
The department identified the firefighters who died as: Captain EMT Matthew Renaud, 35; Engineer Operator EMT Robert Bebee, 41; Firefighter EMT Robert Garner, 29; and Probationary Firefighter Anne Sullivan, 24.
Sullivan had graduated from the Houston Fire Department Academy in April. Renaud and Bebee joined the department in 2001 and Garner in 2010.
"Houston firefighters mourn the loss of our three brothers and our sister and will forever honor their sacrifices," Jeff Caynon, president of the Houston Professional Fire Fighters Association, said in a statement.
Houston Mayor Annise Parker said, "There is nothing we can do that will heal the hurt that we all feel today," and added that the city would honor those who died.